Field of the Invention
The present application relates to a solid form of (R)-N-(4-aminophenethyl)-2-hydroxy-2-
phenylacetamide or salt thereof has purity more than or equal to 99 % when measured by
HPLC and its process for the preparation.
Background of the invention
Mirabegron (formerly YM- 178) is an orally active β-3 adrenoceptor agonist developed by
Astellas pharma for the potential treatment of urinary frequency, urinary incontinence, or
urgency associated with overactive bladder.
Mirabegron is chemically described as (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-
phenylethyl)amino]ethyl] acetanilide (henceforth "Mirabegron") and has the structural
formula I:
NH
O
S
N
NH2
NH
H OH
Formula-I
Mirabegron or a pharmaceutically acceptable salt thereof was first described in U.S. Patent
No. 6,346,532 with its process for the preparation. The other process of Mirabegron and
intermediates thereof is also elaborated in several patents and applications, e.g. U.S. Patent
No. 7,342,117; WO2015/044965; CN103193730, CN 104016877, CN 103232352 and IN
1433/MUM/2014.
Even though, the above mentioned prior art discloses diverse processes for the preparation of
Mirabegron and their intermediates, they are often not amenable on commercial scale
because of expensive reagents, pressure reactions, longer hours reactions and low yield and
purity.
Hence, there remains a need to provide simple, cost effective and scalable processes for the
preparation of intermediate of Mirabegron, involving commercially viable reagents and
starting materials.
3
Summary of the Invention
One of the embodiment of present invention relates to a solid form of (R)-N-(4-
aminophenethyl)-2-hydroxy-2-phenylacetamideor salt thereof, compound of formula III
NH2
HN
OH
O
Formula-III
has purity more than or equal to 99 % when measured by HPLC.
Another embodiment of the present invention relates to the use of solid form of (R)-N-(4-
aminophenethyl)-2-hydroxy-2-phenylacetamideor salt thereof, as a reference standard in
analytical technique such as HPLC method.
One another embodiment of the present invention provides a process for the preparation of
(R)-N-(4-aminophenethyl)-2-hydroxy-2-phenylacetamide or salt thereof, compound of
formula III,
NH2
HN
OH
O
Formula-III
has purity more than 99 % or equal to, when measured by HPLC, the process comprises the
steps of
a) adding (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl-2-phenylacetamide or salt
thereof in alcohol solvent at suitable temperature,
b) adding oxidizing agent or additive to the reaction mixture of step (a),
c) contacting reducing agent to the reaction mixture of step (b) at suitable
temperature,
d) refluxing the reaction for suitable time period and temperature
e) isolation of (R)-N-(4-aminophenethyl)-2-hydroxy-2-phenylacetamide by means of
acid treatment.
4
Another embodiment, the present invention provides a process for the preparation of (R)-N-
(4-aminophenethyl)-2-hydroxy-2-phenylacetamide or salt thereof, which comprises reaction
of (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl-2-phenylacetamide with reducing agent in
presence of oxidative agent or additive.
Another embodiment, the present invention provides a process for the preparation of (R)-N-
(4-aminophenethyl)-2-hydroxy-2-phenylacetamide or salt thereof, which comprises reaction
of (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl-2-phenylacetamide with sodium borohydride in
presence of oxidative agent or additive.
Another embodiment, the present invention provides a process for isolation of (R)-N-(4-
aminophenethyl)-2-hydroxy-2-phenylacetamide or salt thereof having purity more than or
equal to 99%, which comprises
i) providing solution or suspension of (R)-N-(4-aminophenethyl)-2-hydroxy-2-
phenylacetamide in ester solvent;
ii) treating the reaction mixture of step (i) with an acid; and
iii) recovery of the solid of step (ii).
The compound (R)-N-(4-aminophenethyl)-2-hydroxy-2-phenylacetamide or salt thereof
obtained from the present invention can be converted to Mirabegron or a pharmaceutically
acceptable salt thereof according to the prior art processes.
Description of the Invention
One embodiment of the present invention provides a solid form of (R)-N-(4-
aminophenethyl)-2-hydroxy-2-phenylacetamide or salt thereof, compound of formula III
NH2
HN
OH
O
Formula-III
has purity more than 99 % when measured by HPLC.
5
Another embodiment of the present invention provides a process for the preparation of (R)-
N-(4-aminophenethyl)-2-hydroxy-2-phenylacetamide or salt thereof, compound of formula
III
NH2
HN
OH
O
Formula-III
has purity more than 99 %, when measured by HPLC, the process includes the steps of
a) adding (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl-2-phenylacetamide or salt
thereof in alcohol solvent at suitable temperature,
b) adding oxidizing agent or additive to the reaction mixture of step (a),
c) contacting reducing agent to the reaction mixture of step (b) at suitable
temperature,
d) refluxing the reaction for suitable time period and temperature
e) isolation of (R)-N-(4-aminophenethyl)-2-hydroxy-2-phenylacetamide by means of
acid treatment.
The salt of present invention is selected from hydrochloride, hydrobromide, sulphate,
phosphate, hydrogen sulphate, and hydrogen phosphate.
The process involves the addition of (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl]-2-
phenylacetamide or salt thereof in alcoholic solvent at suitable temperature, followed by
addition of suitable oxidizing agent or additive, wherein addition of oxidizing agent or
additive in the form of solution in miscible solvent. The reaction mixture is stirred for the
period of 0.5 hour to 3 hours, followed by lot wise addition of reducing agents, like sodium
borohydride at temperature of about 5°C to 10°C. The reaction mixture is allowed to come to
room temperature and stirred for one hour. The reaction mixture is subjected forreflux for the
period of one hour.
The well known synthetic chemistry discloses that the reduction of nitro group to amine by
using palladium/carbon, Raney Nickel, palladium hydroxide-carbon, platinum oxide,
rhodium on carbon in presence of hydrogen gas or hydrogen generating source like
ammonium formate, hydrazine hydrate and autoclave. However, the use of routine reagents
as per the general chemistry are unfriendly and leads to low yield and purity. Hence, the
6
present inventors found simple and cost effective reducing agent such as sodium borohydride or lithium aluminium hydride. Further, the inventors of the present invention found that the use of oxidative agent or additive along with reducing agent enhances the reduction process.
The alcoholic solvent is selected from the group comprising one or more methanol, ethanol, propanol, isopropanol, iso-butanol, tert-butanol or n-butanol and the like.
The suitable temperature for the reaction is about -10ºC to 10ºC, preferably 5ºC. The suitable time period is about 1 hour to 2 hours.
An oxidizing agent is chemical species, which is commonly used in chemical and pharmaceutical industry that removes an electron from another species. It is one component in an oxidation–reduction reaction. In the second sense, an oxidizing agent or an oxidizer is a chemical species that transfers electronegative atoms, usually oxygen, to a substrate. The oxidizing agents or additive is selected from metal salt such as cupric sulphate (copper sulphate), zinc chloride, cobalt chloride, cerium chloride, calcium chloride, sulfur, zirconium chloride, diethyl selenium bromide, titanium tetrachloride, tin chloride, manganese chloride, aluminium oxide, borontrifluoride-etherate, trimethyl silyl chloride, halogen such as Iodine; acid such as sulfuric acid, acetic acid, trifluoroacetic acid; and Amberlyst-15(H+). The oxidizing agent or additive is added as a solution, preferred solution is cupric sulphate in water.
The suitable temperature is about -10 °C to +10 °C, preferably about -5 °C to +5 °C.
After completion of reaction, the reaction mixture is cooled to room temperature and filtered through celite bed. The filtrate is extracted with ethyl acetate solvent and washed the organic layer with water. Water may be added again to the organic layer.
The acid is added to the reaction mixture and stirred for 15 minutes to 2 hours to enhance the precipitation of solid and purity.
Another embodiment, the present invention provides a process for the preparation of (R)-N-(4-aminophenethyl)-2-hydroxy-2-phenylacetamide or salt thereof, which comprises reaction
7
of (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl-2-phenylacetamide with reducing agent in presence of oxidative agent.
The quantity of reducing agent may be in the range of about 2 to about 10 molar equivalents per mole of (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl-2-phenylacetamide or its salt.
Another embodiment, the present invention provides a process for the preparation of (R)-N-(4-aminophenethyl)-2-hydroxy-2-phenylacetamide or salt thereof, which comprises reaction of (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl-2-phenylacetamide with sodium borohydride in presence of oxidative agent.
The quantity of sodium borohydride may be in the range of about 2 to about 10 molar equivalents per mole of (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl-2-phenylacetamide or its salt.
The oxidative agent is selected from cupric sulfate, halogen such as iodine, calcium chloride, zinc chloride, cobalt chloride, acid and the like. The acid can be sulfuric acid, acetic acid, trifluoroacetic acid and the like.
Another embodiment, the present invention provides a process for isolation of (R)-N-(4-aminophenethyl)-2-hydroxy-2-phenylacetamide or salt thereof having purity more than or equal to 99%, which comprises:
i) providing solution or suspension of (R)-N-(4-aminophenethyl)-2-hydroxy-2-phenylacetamide in solvent;
ii) treating the reaction mixture of step (i) with an acid; and
iii) filtration of the solid of step (ii).
The solvent that may be used in the process of step i) includes but are not limited to ester such as ethyl acetate, methyl acetate and the like; chlorinated solvents such as dichloromethane, dichloroethane, chloroform and the like.
The solution or suspension of (R)-N-(4-aminophenethyl)-2-hydroxy-2-phenylacetamide can be obtained by the dissolution or mixing of (R)-N-(4-aminophenethyl)-2-hydroxy-2-
8
phenylacetamide in solvent, or it may be obtained from a previous processing step where the
(R)-N-(4-aminophenethyl)-2-hydroxy-2-phenylacetamide is formed in solution.
The obtained solution or suspension treated with an acid. The acid may be selected from
hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid acetic acid, formic acid,
trifluoracetic acid and the like.
The acid used in the step (ii) may be added to the solution or suspension at a temperature of
about -10 to about 30 ◦C. Preferably, 10 to 15 ◦C. The solution or suspension can be stirred
for about 15 minutes to 2 hours or more, or longer, to enhance the crystallization.
The obtained solid may be recovered from the reaction mixture by filtration by gravity or by
suction, centrifugation, decantation, and the like. After isolation, the solid may optionally
washed with a suitable solvent.
The obtained solid of (R)-N-(4-aminophenethyl)-2-hydroxy-2-phenylacetamide or salt
thereof has purity more than or equal to 99% by HPLC.
The scheme-1 depicts overall route of synthesis of (R)-N-(4-aminophenethyl)-2-hydroxy-2-
phenylacetamideor salt thereof
NO2
HN
OH
O NH2
HN
OH
O
Formula-II Formula-III
NH
O
S
N
NH2
HN
H OH
Mirabegron
Oxidizing
Agent
Reducing
Agent
Scheme-1
9
The compound (R)-N-(4-aminophenethyl)-2-hydroxy-2-phenylacetamideor salt thereof can be converted into to Mirabegron or a pharmaceutically acceptable salt thereof by means of method disclosed in the art, e.g. US 7,342,117, CN 103193730 and WO 2014132270.
The embodiments of the specification are further illustrated by way of following examples, which do not limit the scope of the claims. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the claims.
Examples
Example-1: Preparation of(R)-2-hydroxy-N-[2-(4-nitrophenyl) ethyl]-2-phenylacetamide
To a mixture of 4-nitrophenylethylamine mono-hydrochloride (10 g), (R)-mandelic acid (7.5 g), trimethylamine (5 g), N,N-dimethylformamide (37ml), hydroxybenzotriazole (6.57 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide mono-hydrochloride (EDC-HCl) (9.4 g) were added and the reaction mixture was stirred at a temperature of about 25°C to 35°C for the period of 2 hours. The reaction mixture was stirred for 2 hours, followed by addition of 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.5 g). The reaction mixture was stirred at room temperature overnight. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed successively with 1M hydrochloric acid aqueous solution (100 ml), 20% potassium carbonate aqueous solution (100 ml) and water (100 ml). The reaction mixture was concentrated under vacuum at 25°C to 35°C. The residue was dissolved in toluene (60 ml). The reaction mixture was heated at temperature of about 85°C to 90°C. The reaction mixture was cooled at temperature of about 25 °C to 35°C to obtain (R)-2-hydroxy-N-[2-(4-nitrophenyl) ethyl]-2-phenyl acetamide, which was further investigated by 1H-NMR spectroscopy and Fourier Transform Infrared Spectroscopy (FTIR).
Yield:95 %
HPLC Purity:≥ 99%
Example-2: Preparation of (R)-N-(4-aminophenethyl)-2-hydroxy-2-phenylacetamide hydrochloride
To a stirred solution of (R)-2-hydroxy-N-[2-(4-nitrophenyl) ethyl]-2-phenylacetamide (5 g) in methanol (50 ml) at temperature of about 3°C, cupric sulphate solution (8.3 g in 25 ml
10
water) was added. The sodium borohydride (3.1 g) was added lot wise added to reaction mixture at a temperature of about 5°C. The reaction was slowly allowed to come to temperature of about 25 °C to 35°C within a period of one hour. The reaction mixture was again charged with sodium borohydride (1.6 g) in lots. The reaction mixture was refluxed for an hour. After completion of reaction, the reaction mixture was cooled at temperature of about 25 °C to 35°C and the reaction mixture was filtered through celite bed. The filtrate was extracted with ethyl acetate (100 ml), and washed with water (100 ml). The organic layer was concentrated to get solid. Ethyl acetate (10 ml) and concentrated hydrochloric acid (3 ml) were charged to it at 10-15 °C and stirred for 1-2 hour. The obtained solid was filtered to get (R)-N-(4-aminophenethyl)-2-hydroxy-2-phenylacetamide hydrochloride, which was further investigated by 1H-NMR spectroscopy and Fourier Transform Infrared Spectroscopy (FTIR).
Yield:98 %
HPLC Purity:≥ 99%
1H-NMR spectroscopy: 1H NMR was performed using Bruker-400 MHz instrument. DMSO-d6 was used as solvent for preparing sample for 1H NMR spectroscopy.
FTIR: Infra-red Spectroscopy was performed using Perkin- Elmer spectrophotometer using pellets with potassium bromide
Figures:
Figure 1 shows the 1H-NMR spectrum of (R)-2-hydroxy-N-[2-(4-nitrophenyl) ethyl]-2-phenyl acetamide.
Figure 2 shows the IR spectrum of (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl]-2-phenyl acetamide.
Figure 3 shows the 1H-NMR spectrum of (R)-N-(4-aminophenethyl)-2-hydroxy-2-phenylacetamide.
Figure 4 shows the IR spectrum of (R)-N-(4-aminophenethyl)-2-hydroxy-2-phenylacetamide.

We Claim:
1. A solid form of (R)-N-(4-aminophenethyl)-2-hydroxy-2-phenylacetamide or salt thereofhaving purity more than or equal to 99% by HPLC.
2. A process for the preparation of (R)-N-(4-aminophenethyl)-2-hydroxy-2-phenylacetamide or salt thereof, has purity more than 99 %, when measured by HPLC, the process the process comprises the steps of
a) adding (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl-2-phenylacetamide or salt thereof in alcoholic solvent at suitable temperature,
b) adding oxidizing agent or additive to the reaction mixture of step (a),
c) contacting reducing agent to the reaction mixture of step (b) at suitable temperature,
d) refluxing the reaction for suitable time period and temperature
e) isolation of (R)-N-(4-aminophenethyl)-2-hydroxy-2-phenylacetamide or salt thereof by means of acid treatment.
3. The process according to claim 2, wherein alcoholic solvent agent is selected from the group comprising one or more of methanol, ethanol, isopropanol and n-butanol.
4. The process according to claim 2, wherein oxidizing agent or additive is selected from one or more of cupric sulphate (copper sulphate), zinc chloride, cobalt chloride, Iodine and acid.
5. The process according to claim 2, wherein acid are selected from one or more sulfuric acid, acetic acid or trifluoro acetic acid.
6. The process according to claim 2, wherein reducing agent is selected from the group comprising one or more of lithium aluminium hydride, sodium cyanoborohydride, sodium triacetoxy borohydride or sodium borohydride.
7. The process according to claim 2, wherein suitable temperature period is about -10°C to 10°C
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8. The process according to claim 2, whereinsuitable time period is about 1 hour to 2 hours.
9. The process according to claim 2, wherein acid treatment is carried out by means of use of an acid.
10. The process according to claim 2, wherein(R)-N-(4-aminophenethyl)-2-hydroxy-2-phenylacetamide further converted to Mirabegron or a pharmaceutically acceptable salt thereof.